On the time scale of milliseconds to minutes synapses are dynamically regulated in ways that are vital to brain function. Such short-term synaptic plasticity has many potential functional roles including rapid computation, coincidence detection, improving temporal precision, dynamic gain control, frequency-dependent filtering, sensory adaptation, and increasing information transfer. However, many aspects of synaptic modification under physiological conditions are poorly understood because synaptic strength during realistic activity patterns reflects the complex interaction of multiple processes. The overall goals of this project are to understand individual mechanisms of synaptic modulation, to determine how these processes combine to control synaptic strength under physiological conditions, and to determine the functional significance of short-term synaptic plasticity. Initially, individual mechanisms of use-dependent plasticity will be studied, such as presynaptic depression of release, facilitation, desensitization of postsynaptic receptors and postsynaptic receptor saturation. In addition, modulation via chemical messenger activation of presynaptic ionotropic and metabotropic receptors will be examined. The manner in which these forms of plasticity interact to control release during physiological patterns of activity will then be determined. Finally, we will determine the functional consequences of short-term synaptic plasticity and evaluate the manner in which plasticity at different types of synapses is tailored to particular roles. Experiments will be conducted in brain slices from rats and mice. Studies of individual mechanisms will use whole-cell voltage clamp recordings of synaptic strength and mEPSC frequency, optical measurement of pre-and post-synaptic calcium and presynaptic waveforms, and serial electron microscopy. Functional consequences of short-term synaptic plasticity will be determined using activation patterns and experimental conditions that approximate physiological conditions. Responses will be measured in current clamp and further characterization will be made in dynamic clamp. All of the techniques required in this study are routinely used in the laboratory, making it likely that the proposed experiments will be completed in the allocated time. These studies will lead to a deeper understanding of the factors controlling the strength of central synapses, and they are relevant for understanding complex conditions including epilepsy, schizophrenia and depression.